Targeting Affective Mood Disorders With Ketamine to Prevent Chronic Postsurgical Pain

Abstract

The phencyclidine-derivative ketamine [2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one] was added to the World Health Organization's Model List of Essential Medicines in 1985 and is also on the Model List of Essential Medicines for Children due to its efficacy and safety as an intravenous anesthetic. In sub-anesthetic doses, ketamine is an effective analgesic for the treatment of acute pain (such as may occur in the perioperative setting). Additionally, ketamine may have efficacy in relieving some forms of chronic pain. In 2019, Janssen Pharmaceuticals received regulatory-approval in both the United States and Europe for use of the S-enantiomer of ketamine in adults living with treatment-resistant major depressive disorder. Pre-existing anxiety/depression and the severity of postoperative pain are risk factors for development of chronic postsurgical pain. An important question is whether short-term administration of ketamine can prevent the conversion of acute postsurgical pain to chronic postsurgical pain. Here, we have reviewed ketamine's effects on the biopsychological processes underlying pain perception and affective mood disorders, focusing on non-NMDA receptor-mediated effects, with an emphasis on results from human trials where available.

Keywords: HCN channel; dissociation; ketamine; oceanic boundlessness; out-of-body experience; pain.

Conflict of interest statement

PG is a co-inventor on patents related to the development of alkylphenols for the treatment of neuropathic pain and both PG and DW serve on the Scientific Advisory Board for Akelos, Inc., a research-based biotechnology company that has secured a licensing agreement for the use of those patents.

Copyright © 2022 Willis and Goldstein.

Figures

Figure 1

Ketamine structure. Ketamine [2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one] contains a chiral center at C-2 of the cyclohexanone ring (numbered as shown), which gives rise to the two stereoisomers shown.

Figure 2

Primary metabolites of ketamine. Ketamine exists in (S) and (R) configurations (see Figure 1). Each is metabolized to several primary metabolites, with the relevant hepatic enzymatic pathways shown in red (primary pathways are indicated by solid arrows, secondary/minor pathways by dotted arrows). Data from (9, 10).

Figure 3

Neuroanatomical and functional networks relevant to ketamine's dissociate properties. (A) Map illustrating the relative anatomic position of the temporoparietal junction (TPJ) and the inferior parietal lobe (IPL). Maps are depicted on the flattened brain surface of the PALS atlas (109). Legend and image modified from Geng and Vossel (110) Figure 2 with permission under the terms of the Creative Commons Site License (https://creativecommons.org/licenses/by/4.0/). (B) Relevant structures that comprise the posterior medial cortex (PMC) as determined by whole-brain activation profiles. Image modified from Bzdok et al. (111) Figure 4 with permission. (C) Shown are two dissociated networks (A and B) near the default mode network (DMN) in a single subject. The dashed boxes highlight nine cortical zones where neighboring representations of the two networks were found, including: 1) dorsolateral prefrontal cortex (PFC), 2) inferior PFC, 3) lateral temporal cortex, 4) inferior parietal lobule (IPL) extending into the temporoparietal junction (TPJ), 5) posteromedial cortex (PMC), 6) midcingulate cortex, 7) dorsomedial PFC, 8) ventromedial PFC, and 9) anteromedial PFC. Note the proximity of zones 4 (TPJ/IPL) and 5 (PMC). Legend and image modified from Braga and Buckner (112) Figure 3 with permission under the terms of the Creative Commons Site License (https://creativecommons.org/licenses/by/4.0/). (D) Regions of interest that form the default mode network. Image modified from Krönke et al. (113) Figure 1 with permission.